Spinal beta-amyloid1-42 acts as an endogenous analgesic peptide in CCI-induced neuropathic pain

Background The mechanism for reduced pain sensitivity associated with Alzheimer's disease (AD) has not been illustrated. We hypothesize that amyloid beta 1-42 (A beta 1-42) in the spinal cord acts as an endogenous analgesic peptide to suppress pain induced by nerve injury. Methods We used chronic constriction injury of the sciatic nerve (CCI) to produce neuropathic pain in Sprague-Dawley rats. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to determine the level of A beta 1-42, the expression of Wnt3a/5b and glial activation in the spinal cord. Western blotting was used to determine the expression of interleukins, the phosphorylation of NR2B and ERK1/2, and the nuclear accumulation of transcriptional factors YAP/TAZ. Thermal hyperalgesia and mechanical allodynia were assessed after CCI and pharmacological manipulations through intrathecal administration. Results Nerve injury increases spinal level of A beta 1-42, while intrathecal administration of MK-8931 reduces the level of A beta 1-42 and facilitates mechanical allodynia. Intrathecal administration of A beta 1-42 suppresses pain behaviors in the early and late phases of neuropathy. Spinal administration of A beta 1-42 regulates the expression of interleukins, reducing glial activation and phosphorylation of NR2B and ERK1/2 in the spinal cord of CCI rats. Furthermore, intrathecal administration of A beta 1-42 decreases Wnt5b expression and suppresses the nuclear accumulation of YAP and TAZ. Blocking the interaction between A beta 1-42 and Frizzled receptors by cSP5 reverses the analgesic effects of A beta 1-42. Conclusions These findings suggest that spinal A beta 1-42 acts as an endogenous analgesic peptide through regulating cytokines and Wnt pathways. This study may provide a potential target for the development of novel analgesic peptides. Significance This study provides an explanation of reduced pain sensitivity associated with Alzheimer's disease. Furthermore, our findings propose a possible physiological function of beta-amyloid1-42 to regulate pain. This study may provide a potential target for the development of novel analgesics based on an existing endogenous peptide.